The Gulf Journal of Oncology

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2 The Gulf Journal of Oncology ISSUE 17 JANUARY 2015 Table of Contents Original Articles /Studies Impact of BMI on Locoregional Control among Saudi Patients with Breast Cancer after Breast Conserving surgery and Modified Radical Mastectomy E.F. Al Saeed, A.J. Al Ghabbban, M.A. Tunio A statistical quantification of radiobiological metrics in Intensity Modulated Radiation Therapy evaluation A. Surega, J. Punitha, S. Sajitha, BS Ramesh, A. Pichandi, P. Sasikala A method for assessment of radiation treatment chain of cervical cancer with combined external and brachy radiation therapy A. Chaparian, P. Shokrani Role of Lymphadenectomy and Its Impact On Survival In Endometrial Carcinoma An Institutional Experience S. Suchetha, P. Rema, S. Vikram, P.S. George, I. Ahmed Breast Cancer Epidemiology, Risk Factors and Tumor Profiles in Bangladeshi underprivileged women M. Rahman, A. Ahsan, F. Begum, K. Rahman Early hematological effects of chemo-radiation therapy in cancer patients and their pattern of recovery- A prospective single institution study H.N. Lee, M.K. Mahajan, S. Das, P. Jeyaraj, J. Sachdeva, M.S. Tiwana Platinum-based chemotherapy in metastatic triple negative breast cancer: Experience of a tertiary referral centre in India V.V. Maka, H. Panchal, S.N. Shukla, S.S. Talati, P.M. Sha, K.M. Patel, A.S. Anand, S.A. Shah, A.A. Patel, S. Parikh A Single Institution 18-Years Retrospective Analysis of Malignant Melanoma A. Mukherji, A.K. Rathi, P.K. Mohanta, K. Singh MRI and ultrasonography for assessing multifocal disease and tumor size in breast cancer: Comparison with histopathological results V. Rudat, A. Nour, N. Almuraikhi, I. Ghoniemy, I. Brune-Erber, N. Almasri, T. El-Maghraby Patient s Compliance On the Use of Extended Low Molecular Weight Heparin Post Major Pelvic Surgeries in Cancer Patients at King Hussein Cancer Center M. Baba, M. Al Masri, M. Salhab, M. El Ghanem Can we use Sorafenib for advanced Hepatocellular Carcinoma (HCC) Child Pugh B? K. Rasul, A. Elessam, S. Elazzazi, R. Ghasoub, A. Gulied Case Reports The external auditory canal as an unusual site for metastasis of breast carcinoma: A case report B.A. Baraka, B.J. Al Bahrani, S.S. Al Kharusi, I. Mehdi, A.M. Nada, N.H. Al Rahabi Primary Mixed Cellularity Classical Hodgkin lymphoma of the Lumbar spine An unusual presentation K.R. Anila, R. A. Nair, S. Prem, K. Ramachandran Subdural hematoma during therapy of gastro-intestinal stromal tumor (GIST) with Imatinib mesylate J. Feki, G. Marrekchi, T. Boudawara, N. Rekik, S. Maatoug, Z. Boudawara, M. Frikha Conference Highlights /Scientific Contribution Workshop Highlights The Second Regional Training Of The Trainers (TOT) Workshop On Palliative Care, Kuwait, November News Notes Advertisements Scientific events in the GCC and the Arab World for the 1 st Semester of

3 Impact of BMI on Locoregional Control among Saudi Patients with Breast Cancer after Breast Conserving surgery and Modified Radical Mastectomy E. F. Al Saeed 1, A. J. Al Ghabbban 1, M. A. Tunio 2 1 King Saud University, Riyadh, Saudi Arabia 2 King Fahad Medical City, Riyadh, Saudi Arabia Abstract Obesity and increased body mass index (BMI) are increasing among Saudi women across all age groups with an overall prevalence of 44%. Increased BMI is associated with advanced stage breast cancer and dismal survival; however impact of BMI on locoregional control (LRC) is less studied. We aimed to evaluate the impact of BMI on LRC in Saudi patients with breast cancer after breast conserving surgery (BCS) and modified radical mastectomy (MRM). Materials and methods: Between February 1988 and August 2008, 112 patients with breast cancer were treated with BCS and MRM followed by adjuvant chemotherapy and radiotherapy. Median age was years (23-76). Mean BMI was 38.1 kg/m 2 ( ); BMI < 18.5 kg/m 2 (underweight) in 1 (0.9%), BMI kg/m 2 (normal weight) in 19 (16.9%), BMI kg/ m2 (overweight) in 32 (28.6%), BMI kg/ m2 (obese) in 48 (42.9%) and BMI > 40 kg/m 2 (morbid obese) in 12 (10.7%). Median follow Introduction Obesity and overweight (body mass index >26 kg.m 2 ) are increasing among both sexes and across all age groups in the Kingdom of Saudi Arabia with an overall prevalence of 44% in Saudi women (1). Obesity is known as the major factor for development of breast cancer which is the most common malignancy in Saudi Arabia accounting for 26% of all newly diagnosed breast Corresponding Author: Mutahir A. Tunio, MBBS, FCPS (Radiation Oncology), Assistant Consultant, Radiation Oncology, King Fahad Medical City, Riyadh, Saudi Arabia. Tel: , Fax: drmutahirtonio@hotmail.com 7 up period was 9 years (5-17). Cox proportional hazard analysis was done using SPSS Results: A total of ten locoregional recurrences (8.93%) were seen. The 5 and 10 years LRC were 86.4% and 86.4% respectively. Multivariate analysis showed poor LRC in BMI <18.5 kg/m 2 (HR: 4.2; 95% CI , p 0.001) and kg/m 2 (HR: 3.4; 95% CI , p 0.01). Others factors associated with poor LRC were: age less than 40 years, premenopausal status, and no adjuvant radiotherapy, and T4, N2 and N3 stages. Conclusion: Underweight patients with breast cancer are more prone for locoregional recurrences as compared to obese and morbid obese patients. Key words: Body mass index, breast cancer, breast conserving surgery, modified radical mastectomy cancers in Saudi women and with incidence of 21.6 per 100,000 (2). Some studies have revealed a clear positive association between increased body mass index (BMI) and risk of developing breast cancer by 30-50% (3, 4). Elevated BMI has been shown to be associated with a poorer prognosis in breast cancer patients regardless of the menopausal status and increased mortality from other obesity-driven health problems (5), but retrospective data failed to show any impact of BMI on post treatment locoregional recurrence (LRR) in breast cancer patients (6,7,8). Recently, results from a French trial have shown that breast cancer patients with

4 Impact of BMI on Locoregional Control in Breast Cancer, E.F. Al Saeed, et. al. low BMI are at high risk of LRR after breast conserving surgery (BCS) followed by adjuvant chemotherapy and radiotherapy (9). However no data addressing direct impact on BMI on LRR in breast cancer patients after modified radical mastectomy (MRM) is available. The purpose of this study was to evaluate the impact BMI on LRR in Saudi patients with breast cancer treated with BCS or MRM followed by adjuvant hormonal, chemotherapy and adjuvant radiotherapy. Materials and Methods After approval from the Institutional Ethical Review Board (IRB) committee, records of 112 patients with breast cancer treated between February 1988 and August 2008 with BCS and MRM followed by adjuvant chemotherapy and radiotherapy were reviewed and comprised the study population. Inclusion criteria were (a) histopathological confirmed breast cancer, (b) T1-T4, N0-N2, (c) underwent BCS or MRM +/- adjuvant hormonal, chemotherapy and radiotherapy. Exclusion criteria were (a) presence of distant metastasis, (b) neoadjuvant chemotherapy and (c) inflammatory or inoperable tumors. BMI calculation Each patient was categorized according to BMI. Height and weight were measured at the time of surgery using institutional protocols and BMI was calculated using the formula of weight in kilograms divided by the square of the height in meters (kg/m 2 ). BMI was then categorized into five groups as follows: underweight as BMI < 18.5 kg/m 2 ; normal weight as BMI from 18.5 to 25 kg/m 2 ; overweight as BMI from 25 to 30 kg/m 2 ; obese as BMI from 31 to 40 kg/m 2 and morbid obese as BMI above 40 kg/m 2. Clinical and histologic variables likely to influence the risk of LRR studied were the following: Clinical variables Age, menopausal status, associated comorbidities, BMI groups, initial tumor size on physical, mammography and sonography 8 examination, laterality and location of primary tumor. Surgery was performed either wide local excision or MRM with axillary lymph node dissection. Adjuvant chemotherapy or hormonal therapy was given 4-5 weeks after surgery followed by radiotherapy. Histopathological variables Histopathological types of tumors according to WHO 1981 classification of breast tumors, grade according to Scarff Bloom and Richardson classification, pathological size of tumor, presence/absence of estrogen receptors (ER), progesterone receptors (PR), Her 2 neu overexpression, number of retrieved axillary lymph nodes and number of positive nodes, nodal density, presence of lymphovascular space invasion (LVSI) and margin status (negative or positive). Statistical analysis The primary endpoints were LRR and locoregional control (LRC). Secondary endpoints were disease free survival (DFS) and overall survival (OS). The time period from last follow up evaluation, appearance of local relapse and death were calculated from date of starting treatment. LRR was defined as any recurrence of tumor within the treated breast, chest wall or ipsilateral axilla and overlying skin. Skin recurrence was considered as local failure when located exclusively in ipsilateral breast or chest wall. Local recurrences occurring synchronously with distant metastasis were also included. DFS was defined as the duration between the entry date and the date of documented disease reappearance, death from cancer and/or last follow-up (censored). OS was defined as the duration between the entry date and the date of patient death or last follow-up (censored). Probabilities of LRC and DMC, DFS and OS were determined with the Kaplan-Meier method. The comparisons for various endpoints were performed using log rank test and Cox regression analysis. Univariate and multivariate analyses were also performed for different prognostic factors for LRR. All statistical analyses were performed using the computer program SPSS version 19.0.

5 Results G. J. O. Issue 17, 2015 Median follow up period was 9 years (range: 5-17). Patients characteristics according to BMI subgroups are shown in Table 1. 9

6 Impact of BMI on Locoregional Control in Breast Cancer, E.F. Al Saeed, et. al. Table 1: Patients characteristics according to body mass index groups Abbreviations: DM= diabetes mellitus, HTN= hypertension, HL= hyperlipidemia, T=Tumor, N=Nodes, IDC=infiltrating ductal carcinoma, ILC= invasive lobular carcinoma, LVSI= lymphovascular space invasion, ER= Estrogen receptors, PR= Progesterone receptors, BCS= breast conservation surgery, MRM=modified radical mastectomy Clinical characteristics Mean age of cohort was 47.0 years (range: 23-76; standard deviation (SD) 10.3). According to menopausal status, 93 patients (83.0%) were premenopausal and 19 patients (17.0%) were postmenopausal. Mean BMI was 31.8 kg/m2 (range: ;SD7.2). According to comorbidities, 72 patients (64.3%) have no comorbidities. Common morbidities in 40 patients (35.7%) were: hypertension in 14 patients (12.5%), diabetes in 9 patients (8.0%) and combined hypertension and diabetes in 6 patients (5.4%). Family history was positive in 17 patients (15.2%). In four patients (3.6%) there were bilateral breast cancer at the time of diagnosis. Majority of cohort (57 patients; %) had left side breast cancer and outer lower quadrant was common site of tumor location (50 patients; 45.9%) followed by upper outer quadrant (30 patients; 27.5%). Mean mammography size of tumor was 3.9 cm (range: 1-7;SD 2.3). Mean baseline CA15.3 level was 31.1 units/ml (range: ;SD 23.9) Histopathological characteristics Mean pathological tumor size was 3.4 cm (range: 1-10; SD 2.4) and infiltrating ductal carcinoma (IDC) was predominant histopathological variant seen in 95 patients (88.0%). Majority of tumors were moderately differentiated of grade 2 (68 patients;60.7%). According to marginal status, 77 patients (68.8%)

7 had negative margins. Majority of cohort was ER and PR positive (65 patients;58.0%) and Her 2 neu overexpression was seen in 10 patients (8.9%). Treatment characteristics Majority of patients had MRM (77 patients;71.3%) followed by BCS in 31 patients (28.7%). Mean axillary retrieved lymph nodes were 14.1 (2-42) after axillary dissection and sentinel node dissection. A total of 70 patients (62.5%) received adjuvant chemotherapy which was given within 5-6 weeks (range:3-11) of surgery. Adjuvant chemotherapy protocols were: CMF (18.6%), AC followed Paclitaxal (32.9%), FAC (32.9%), TAC (5.9%), AT (5.7%), FAC+TAC (4%). A total of 89 patients (83.0%) received local radiation therapy which was started 22 weeks (18-26) after the surgery and 3-5 weeks after the completion of chemotherapy. For BCS patients, whole breast radiation therapy was delivered in 2Gy fractions to mean total mean dose of 50 Gy (45-64) and for MRM patients, chest wall radiation therapy was given in 2 Gy fractions to mean total dose 50Gy (50-60). For positive axillary nodes, supra-clavicular fields were used and given mean total dose of 45 Gy ( ). All patients were treated using three dimensional conformal radiation therapy (3DCRT) and on multileaf collimator (MLC) assisted linear accelerator. Hormonal therapy was given to 66 patients (8.9%) in the form of tamoxifen (46.4%), letrozole (9.8%) and sequential regimen in 9.8%. Mean duration of hormonal therapy was 5.5 years (range; ). G. J. O. Issue 17, 2015 Figure 1: Cumulative locoregional control in cohort at 5, 10 and 15 years (OS) rates were 74.2% (95% CI: ) and 77.4% (95% CI: ) respectively. Univariate analysis of clinical prognostic factors for LRR in our cohort showed four prognostic factors influencing the LRR: (a) age less than 40 years (HR:4.3, 95% CI: ), (b) Locoregional recurrence, distant control and overall survival A total of 10 locoregional recurrences (8.93%) were seen among 112 breast cancer patients. Four (40%) LRR occurred at scar site and 6 LRR (60%) were seen in ipsilateral axilla and supraclavicular regions. Median time of LRR was 3.6 years (range: ). The actual LRC rates at 10 years were 86.4% (Figure 1). Actual 10 year distant control (DC) and overall survival 11 Table 2: Univariate analysis of clinical prognostic factors for locoregional recurrence in breast cancer patients Abbreviations: CI= confidence interval, BMI= body mass index, BCS= breast conserving surgery, MRM=modified radical mastectomy

8 Impact of BMI on Locoregional Control in Breast Cancer, E.F. Al Saeed, et. al. Table 3: Univariate analysis of histopathological prognostic factors for locoregional recurrence in breast cancer Abbreviations: IDC= infiltrating ductal carcinoma, ILC= invasive lobular carcinoma, LVSI= lymphovascular space invasion, T= primary tumor, N= axillary nodes, CI= confidence interval Table 4. Multivariate analysis of prognostic factors for locoregional recurrence in breast cancer Abbreviations: CI=confidence interval, BMI= body mass index, T= primary tumor size, N= axillary nodal status premenopausal status (HR:3.4, 95% CI: ), (c) BMI below 18.5 kg/m2(hr: 3.2, 95% CI: ) and (d) no adjuvant radiotherapy (HR: 5.2, 95% CI: ) (Table2). Univariate analysis of histopathological prognostic factors for LRR in our cohort showed five prognostic factors influencing the LRR: (a) IDC histological type (HR:2.2, 95% CI: ), (b) stage T4 (HR: 1.8, 95% CI: ), (c) N2 and N3 nodal status (HR:1.8, 95% CI: ), (d) negative ER status (HR:1.2, 95% CI: ) and (e) Her 2neu overexpression (HR:2.1, 95% CI: ) (Table3). In multivariate analysis, age less than 35 years, BMI is below 18.5 kg/m 2, premenopausal status, no adjuvant radiotherapy, T and N stage were still independent important prognostic factors for LRR in our cohort (Table4). 12 Figure 2: Cumulative locoregional control in cohort according to BMI subgroups According to BMI groups, patients with BMIs below 18.5 kg/m 2 followed by overweight (BMI kg/m 2 ) patients had poor LRR in comparison to normal, obese and morbid obese patients (Figure 2).

9 G. J. O. Issue 17, 2015 BMI was not found as prognostic factor for distant control in our cohort. Discussion Breast cancer is the major public health concern in Saudi Arabia as the most common cancer among women with overall percentage of 22.4%. The most common age group found to be affected is years with age-specific incidence of breast cancer of 45 per 100,000 at the age of 45 years (10). Obesity is known as causative factor for the development of breast cancer and is associated with dismal prognosis in breast cancer patients because of delayed diagnosis among overweight women or the growth and spread of breast cancer may be more rapid in obese women and consequently, obese women would tend to have more recurrences (11). In Saudi Arabia 80% of premenopausal women are either overweight or obese which alarms the grave prognosis of breast cancer as compared to other parts of the world (12). However, impact of obesity or increased BMI on locoregional control in breast cancer patients is less studied. Our retrospective data showed two interesting relationships: (a) an inverse association between BMI and LRR and (b) positive relationship between BMI (26-30 kg/m 2 ) and LRR. Then after the risk of LRR markedly reduced in obese (BMI above 31 kg/m 2 ) and morbid obese patients. This could be explained by four hypotheses; (1) Bad clinical and histopathological features in patients with BMI below 18.5 kg/m 2 in our cohort. Thin premenopausal women tend to have more high levels of endogenous estrogen level than obese premenopausal women, which enhances the risk LRR (13). (2) Low sample size of patients with BMI below 18.5 Kg/m 2 (3) Patients below 18.5 kg/m2 have BCS. The relationship between tumor size and breast volume might be another explanation. Women with lower BMI have smaller breast and less adipose tissue which makes it difficult for wide negative margins during lumpectomy (14). (4) In our cohort obese and morbid obese patients had more ER and PR receptors and the use of hormonal therapy is associated with low risk of LRR as compared to overweight patients (15). Strengths of our study were long follow up period and availability of complete data; however our study can be criticized for (a) low sample size especially patient with BMI less than 18.5 kg/m2 and (b) lack of impact of BMI on distant failure which shall be addressed in large prospective trials. In conclusion, underweight patients with breast cancer are more prone for locoregional recurrences as compared to obese and morbid obese patients. For these patients, boost dose to adjuvant radiotherapy can reduce the risk of locoregional failures and this question can be answered more properly in prospective trials on this subject. References 1. Al-Nozha MM, Al-Mazrou YY, Al-Maatouq MA, Arafah MR, Khalil MZ, Khan NB, Al-Marzouki K, Abdullah MA, Al-khadra AH, Al-Harthi SS, Al- Shahid MS, Al-Mobeireek A, Nouh MS. Obesity in Saudi Arabia. Saudi Med Journal 2005;26: Al-Eid HS. Cancer Incidence and Survival Report Saudi Arabia 2007, reports/scr2007.pdf 3. Ursin G, Longnecker MP, Haile RW, et al. A metaanalysis of body mass index and risk of premenopausal breast cancer. Epidemiology 1995;6: Folsom AR, Kaye SA, Prineas RJ, et al. Increased incidence of carcinoma of the breast associated with abdominal adiposity in postmenopausal women. Am J Epidemiol 1990;131: A. R. Carmichael, Obesity and Prognosis of Breast Cancer. Obesity Reviews 2006; 7: Donegan WL, Hartz AJ, Rimm AA: The association of body weight with recurrent cancer of the breast. Cancerc1978; 41:

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